Autophagy represents a fundamental mechanism for maintaining cell survival and tissue homeostasis in response to physiological and pathological stress. Autophagy initiation converges on the FIP200-ATG13-ULK1 complex wherein the serine/threonine kinase ULK1 plays a central role. Here, we reveal that the E3 ubiquitin ligase TRIM27 functions as a negative regulatory component of the FIP200-ATG13-ULK1 complex. TRIM27 directly polyubiquitinates ULK1 at K568 and K571 sites with K48-linked ubiquitin chains, with proteasomal turnover maintaining control over basal ULK1 levels. However, during starvation-induced autophagy, TRIM27 catalyzes non-degradative K6- and K11-linked ubiquitination of the serine/threonine kinase 38-like (STK38L) kinase. In turn, STK38L ubiquitination promotes its activation and phosphorylation of ULK1 at Ser495, rendering ULK1 in a permissive state for TRIM27-mediated hyper-ubiquitination of ULK1. This cooperative mechanism serves to restrain the amplitude and duration of autophagy. Further evidence from mouse models shows that basal autophagy levels are increased in Trim27 knockout mice and that Trim27 differentially regulates tumorigenesis and metastasis. Our study identifies a key role of STK38L-TRIM27-ULK1 signaling axis in negatively controlling autophagy with relevance established in human breast cancer.

中文翻译：

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TRIM27 与 STK38L 协同抑制 ULK1 介导的自噬并促进肿瘤发生

自噬代表了维持细胞存活和组织体内平衡以响应生理和病理应激的基本机制。自噬起始聚集在 FIP200-ATG13-ULK1 复合物上，其中丝氨酸/苏氨酸激酶 ULK1 起着核心作用。在这里，我们揭示了 E3 泛素连接酶 TRIM27 作为 FIP200-ATG13-ULK1 复合物的负调控成分。TRIM27 在 K568 和 K571 位点用 K48 连接的泛素链直接多聚泛素化 ULK1，蛋白酶体转换保持对基础 ULK1 水平的控制。然而，在饥饿诱导的自噬过程中，TRIM27 催化丝氨酸/苏氨酸激酶 38 样 (STK38L) 激酶的非降解性 K6 和 K11 泛素化。反过来，STK38L 泛素化促进 ULK1 在 Ser495 位点的激活和磷酸化，使 ULK1 处于 TRIM27 介导的 ULK1 超泛素化的许可状态。这种合作机制用于抑制自噬的幅度和持续时间。来自小鼠模型的进一步证据表明，Trim27 敲除小鼠的基础自噬水平增加，并且 Trim27 差异​​调节肿瘤发生和转移。我们的研究确定了 STK38L-TRIM27-ULK1 信号轴在负向控制自噬中的关键作用，并在人类乳腺癌中建立了相关性。